Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19

Robinson et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofad355, NCT04535167

Jul 2023

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Phase 1 safety and pharmacokinetic study of lufotrelvir in 25 hospitalized COVID-19 patients. No adverse events or serious adverse events were considered related to lufotrelvir. Concentrations of lufotrelvir and its active moiety increased dose-proportionally, with mean steady-state concentrations of the active moiety above the EC90 for SARS-CoV-2.

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Robinson et al., 10 Jul 2023, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 23 authors, study period September 2020 - May 2021, trial NCT04535167 (history). Contact: sima.toussi@pfizer.com, sudeepta.aggarwal@pfizer.com, sions@oup.com.

This Paper Lufotrelvir All

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19

Philip Robinson, MD Sima S Toussi, Sudeepta Aggarwal, Arthur Bergman, Tong Zhu, Frances Hackman, Jean G Sathish, Lawrence Updyke, Peter Loudon, Ganesh Krishna, Philippe Clevenbergh, Miguel Gorgolas Hernandez-Mora, Jose Miguel Cisneros Herreros, Timothy E Albertson, Michael Dougan, Amber Thacker, Mary Lynn Baniecki, Holly Soares, Mark Whitlock, Gianluca Nucci, Sandeep Menon, Annaliesa S Anderson, Michael Binks

Open Forum Infectious Diseases, doi:10.1093/ofid/ofad355

Background. An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Method. Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results. In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2-and 4-fold that of in vitro EC 90 following 250-and 500-mg doses, respectively. Conclusions. These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies.

Supplementary Data Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the Phase 1 Safety and Pharmacokinetics of PF-07304814 • OFID • 7 Notes Acknowledgments. Medical writing support was provided by Sheena Hunt, PhD, and Allison R. Gillies, PhD, of ICON and was funded by Pfizer. We thank William Reagan, Norimitsu Shirai, Daniel Lettiere, Frank Geoly, and Jeremy Dugas for expert input into the nonclinical studies. We also thank all the participants who volunteered for this study and all the study investigators and site personnel for their contributions to this study. Data sharing. Upon request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/ clinical-trials/trial-data-and-results for more information. Financial support.

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PF-07304814—the prodrug (lufotrelvir) and its active moiety ' '(PF-00835231)—is a potent inhibitor of the SARS-CoV-2 3CL protease.\n' ' \n' ' \n' ' Method\n' ' Eligible participants were 18 to 79 years old and hospitalized with ' 'confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ' 'ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local ' 'standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion ' 'of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion ' 'of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of ' 'lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and ' 'PF-00835231.\n' ' \n' ' \n' ' Results\n' ' In SAD, participants were randomized to receive 250 mg lufotrelvir ' '(n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In ' 'MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir ' '(n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious ' 'adverse events were considered related to lufotrelvir. At doses of 250 and 500\u2005mg, ' 'concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a ' 'dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached ' 'steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg ' 'doses, respectively.\n' ' \n' ' \n' ' Conclusions\n' ' These safety and pharmacokinetic findings support the continued ' 'evaluation of lufotrelvir in clinical studies.\n' ' Clinical Trials Registration. 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